Plastin 3 Is a Protective Modifier of Autosomal Recessive Spinal Muscular Atrophy
Gabriela E. Oprea,1,2,3
Sandra Kröber,1,2
Michelle L. McWhorter,4
Wilfried Rossoll,5
Stefan Müller,3
Michael Krawczak,6
Gary J. Bassell,5
Christine E. Beattie,4
Brunhilde Wirth1,2,3*
Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
1 Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
2 Institute of Genetics, University of Cologne, 50931 Cologne, Germany.
3 Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
4 Centre for Molecular Neurobiology and Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
5 Emory University School of Medicine, Department of Cell Biology, Atlanta, GA 30322, USA.
6 Institute of Medical Informatics and Statistics, Christian-Albrechts University of Kiel, 24105 Kiel, Germany.
* To whom correspondence should be addressed. E-mail: brunhilde.wirth{at}uk-koeln.de
